The BRCA2 c.8168A>C (p.Asp2723Ala, p.D2723A) variant has been reported in ClinVar and is classified as Pathogenic by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.1 This variant is present at very low frequency in population databases, with 1/251098 alleles in gnomAD v2.1 (AF 3.98e-06) and 6/1614162 alleles in gnomAD v4.1 (AF 3.72e-06), which is too low to support a benign frequency criterion but means PM2 is not met because the variant is not absent from controls.2 In the ENIGMA BRCA2 curated functional dataset, calibrated functional studies support PS3 Strong for this variant, indicating a damaging effect on BRCA2 function.3 Computational evidence supports a damaging protein effect because the variant is in the BRCA2 DNA-binding region, BayesDel is 0.575545 above the PP3 threshold of 0.30, REVEL is 0.94, and SpliceAI predicts no significant splice impact (max delta score 0.00).4
Final classification
Likely Pathogenic
PS3PP3PP5
BRCA2
c.8168A>C
p.Asp2723Ala
This variant
The BRCA2 c.8168A>C (p.Asp2723Ala, p.D2723A) variant has been reported in ClinVar and is classified as Pathogenic by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.
ENIGMA BRCA1 and BRCA2 Specification v1.2.0 final-classification framework using Table 3 criteria-combination rules.
Classification rationale
PS3PP3PP5
Likely Pathogenic
BRCA2 c.8168A>C
PS3 + PP3 + PP5
→
Likely Pathogenic
3
vcep_specifications_table9_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18
4
cspec ↗bayesdelrevelspliceai ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 16 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
Pathogenic
In the ENIGMA BRCA2 curated functional dataset, this variant is assigned PS3 Strong because calibrated functional studies showed protein function similar to pathogenic control variants, supporting a damaging effect on BRCA2 function.
Specifications Table 9 exact variant row: BRCA2 c.8168A>C p.(Asp2723Ala)Pre-assigned code in Table 9: PS3 Strong
PP3
supporting
Pathogenic
This missense variant lies within the BRCA2 DNA-binding functional region used by ENIGMA (amino acids 2481-3186) and has a BayesDel score of 0.575545, which is above the PP3 threshold of 0.30. REVEL is also high at 0.94, supporting a deleterious protein effect. SpliceAI predicts no significant splice impact (max delta score 0.00), so the computational evidence supports a damaging protein consequence rather than a splice mechanism.
Variant location p.Asp2723Ala within BRCA2 DNA binding domain aa 2481-3186BayesDel 0.575545REVEL 0.94
Assessed · not applied
· 11 not met · 5 not assessed
Pathogenic
PVS1
This missense variant does not fall into the BRCA2 loss-of-function categories used for PVS1, and SpliceAI predicts no significant splice effect (max delta score 0.00), so available evidence does not support a truncating or RNA loss-of-function mechanism for this change.
PS1
No qualifying reference variant with the same amino acid change and an established BRCA2 protein-based pathogenic classification was identified in the reviewed materials, so PS1 was not applied.
PS4
No case-control evidence showing a statistically increased prevalence of this variant in affected individuals versus controls was identified, and the reviewed ENIGMA posterior-probability and multifactorial resources did not provide an exact variant-specific PS4-qualifying result.
PM2
ENIGMA PM2_Supporting requires absence from gnomAD, but this variant is present in gnomAD v2.1 at 1/251098 alleles (AF 3.98e-06) and in gnomAD v4.1 at 6/1614162 alleles (AF 3.72e-06), so PM2 is not met.
PM3
No evidence was identified that this variant was observed in trans with another BRCA2 pathogenic variant in an individual with BRCA2-related Fanconi anemia, so PM3 could not be assessed.
PP1
No quantitative co-segregation data were identified for this variant, so PP1 could not be applied.
PP4
The BRCA2 clinical-history likelihood ratio for this variant is 1.329 with 2 probands, which falls in the ENIGMA neutral zone above 0.48 and below 2.08, so available clinical-history evidence does not support PP4.
Benign
BA1
This variant is far below the BA1 threshold.
BS1
This variant does not meet the BRCA2 BS1 frequency thresholds.
BS2
No qualifying adult observations or point-based evidence against BRCA2-related Fanconi anemia were identified for this variant, so BS2 could not be assessed.
BS3
Available functional evidence does not support normal BRCA2 function.
BS4
No quantitative lack-of-segregation evidence was identified for this variant, so BS4 could not be applied.
BP1
This missense variant is located within the BRCA2 DNA-binding functional region rather than outside a clinically important domain, so BP1 is not met.
BP4
Although SpliceAI predicts no significant splice impact (max delta score 0.00), the variant is in the BRCA2 DNA-binding region and the BayesDel score is 0.575545, which is above the BP4 benign threshold of 0.18.
BP5
The BRCA2 clinical-history likelihood ratio for this variant is 1.329 with 2 probands, which is above the BP5 supporting cutoff of 0.48 and remains in the ENIGMA neutral zone, so BP5 is not met.
BP7
This is a missense variant within the BRCA2 DNA-binding functional region, and available functional evidence supports a damaging protein effect rather than a benign RNA-only effect, so BP7 is not met.
N/A · 9
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP6
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.7171e-06; MAF= 0.00037%, 6/1614162 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08464e-06; MAF= 0.00051%, 6/1180024 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.98251e-06; MAF= 0.00040%, 1/251098 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.81865e-06; MAF= 0.00088%, 1/113396 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00037%
· 6 / 1,614,162
0 hom · FAF 0.00018%
0 hom · FAF 0.00018%
European (non-Finnish) 6 / 1,180,024 |
0.00051% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004%
· 1 / 251,098
0 hom
0 hom
European (non-Finnish) 1 / 113,396 |
0.00088% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely Pathogenic (1 clinical laboratory) and as Pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.94. BayesDel score = 0.575545.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links